Direct C–H Trifluoromethylation of Glycals by Photoredox Catalysis

Letter pubs.acs.org/OrgLett

Direct C−H Trifluoromethylation of Glycals by Photoredox Catalysis Bang Wang,† De-Cai Xiong,*,† and Xin-Shan Ye*,† †

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Center for Molecular and Translational Medicine, Peking University, Xue Yuan Road No. 38, Beijing 100191, China S Supporting Information *

ABSTRACT: A mild, efficient, and practical transformation for the direct C−H trifluoromethylation of glycals under visible light has been reported for the first time. This reaction employed fac-Ir3+(ppy)3 as the photocatalyst, Umemoto’s reagent as the CF3 source, and a household blue LED or sunlight as the light source. Glycals bearing both electronwithdrawing and -donating protective groups performed this reaction smoothly. This visible light-mediated trifluoromethylation reaction was highlighted by the trifluoromethylation of the biologically important Neu2en moiety.

G

lycans play crucial roles in a variety of physiological and pathological processes.1 Carbohydrate-based drug discovery is a subject of current interest and challenge. Some carbohydrate-based drugs and vaccines have been used to battle infectious diseases, diabetes, and other diseases.2 Modifications are powerful strategies for reducing hydrophilicity and improving the affinity, oral bioavailability, and metabolic stability of native carbohydrates in the realm of carbohydratebased drug discovery.3 Due to the unique properties of the fluorine atom, the incorporation of fluorine into carbohydrates has become one of the most important modification approaches to address such issues.3,4 Trifluoromethyl (CF3) is a useful structural motif in many bioactive molecules and a privileged group in medicinal chemistry, owing to the unique properties of CF3 functionality on organic molecules, including lipophilicity, metabolic stability, high electronegativity, and bioavailability.5 The development of new methodologies for the efficient introduction of a CF3 group into organic compounds has been a hot topic in synthetic chemistry.6 Especially, the photoredoxcatalyzed7 radical trifluoromethylation8 has enabled many mild and efficient methods for trifluoromethylation of alkenes, (hetero)arenes, alkynes, phenol, and many other compounds.9 Photoredox catalytic trifluoromethylation can be easily scaledup using continuous flow technology, making the process more environmentally benign.9b Nonetheless, no general protocols for the modification of carbohydrates have emerged from those research efforts.10 In continuation of our interest in the area of carbohydrate synthesis and carbohydrate-based drug discovery,11 we have now developed a method for the trifluoromethylation of glycals. Glycals are versatile building blocks for the construction of oligosaccharides and glycoconjugates, as well as other bioactive natural products or their derivatives.12 Glycals or their derivatives have also been used as inhibitors or probes for glycosidases13 such as the antiflu drugs Zanamivir,14 Ianinamivir,15 and Oseltamivir16 (Figure 1). In fact, most glycals usually need to be modified to gain better biological functions. However, the modification of glycals has been a formidable © XXXX American Chemical Society

Figure 1. Glycal-derived drugs.

challenge due to the structural complexity of carbohydrate substrates and the inactive electron-deficient double bond of glycals. Herein, we report a direct C−H trifluoromethylation of glycals using visible-light photoredox catalysis. Our initial investigation of the reaction parameters was conducted using the less electron-deficient 6-O-benzyl-3,4dideoxy-glycal 1a as the substrate and a household blue LED as the light source (Table 1, and Table S1 in Supporting Information). We found that Togni reagent 2a,8f Togni reagent 2b, CF3SO2Na, CF3SO2Cl,8j or CF3TMS was not an ideal CF3 source (entries 1−5). However, the desired trifluoromethylated-3,4-dideoxy-glucal 3a was obtained in good yield by the use of either Umemoto reagent 2c (85%) or Umemoto reagent 2d (80%) as the CF3 source (entries 6−7). Different solvents were also tested (entries 8−12, Table S1), and anhydrous DMA was found to be the best choice (entry 13). Further screening of the ratio of reagents (entries 14−16), reaction time (Table S2), additives (Table S3), temperature (Table S4), and photocatalysts7c (entries 17−19) established the optimized conditions: fac-Ir(ppy)3 (1.5 mol %) as catalyst and 2c (1.5 equiv) as CF3 source in DMA under the irradiation of visible light for 1.5 h at room temperature (entry 13, 91%). Control experiments showed that both light and the photocatalyst were essential for the reaction (entries 20−21). Under the optimized reaction conditions, the scope of 3,4dideoxy-glycal (1b−e) with different protective groups was Received: October 18, 2015

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DOI: 10.1021/acs.orglett.5b03016 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Trifluoromethylation of 1a via Photoredox Catalysisa

Scheme 2. Substrate Scope of Trifluoromethylation of Hexose-Derived Glycalsa

entry

“CF3” reagent

solvent

catalyst

yield [%]b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21c

2a 2b CF3SO2Na CF3SO2Cl CF3TMS 2c 2d 2c 2c 2c 2c 2c 2c 2c (1.2 equiv) 2c (2.0 equiv) 2c (5.0 equiv) 2c 2c 2c 2c 2c

DMF DMF DMF DMF DMF DMF DMF CH3CN Et2O DCM DMSO THF DMA DMA DMA DMA DMA DMA DMA DMA DMA

fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 fac-Ir(ppy)3 Ru(bpy)3Cl Ru(bpy)3Cl·6H2O Ru(bpy)3(PF6)2 − fac-Ir(ppy)3

trace trace 0 0 0 85 80 0 0 0 71 0 91 79 91 90 79 77 84 0 0 a

Reaction conditions: 1a (0.10 mmol), “CF3” reagent (0.15 mmol), photocatalyst (1.5 mol %), solvent (1.0 mL), under argon atmosphere, visible light, 1.5 h. bYields determined by 19F NMR using α,α,αtrifluorotoluene as an internal standard. cIn the dark. a

Isolated yield.

yields. The tosyl-protected substrate (product 5e, 68%) and the free hydroxyl-containing substrate (product 5f, 58%) were tolerated under the standard conditions. Trifluoromethylation of the acetylated glucal (product 5d, 49%) or acetylated galactal (product 5j, 63%) gave the desired products in a lower yield, when compared with their benzylated, p-methoxybenzylated, methylated counterparts. This might result from the strong electron-withdrawing effect of the acetyl. An especially encouraging aspect of the chemistry was that the acetylated lactal could also be trifluoromethylated in good yield (product 5q, 68%). To further highlight the value of this transformation, the trifluoromethylation reactions of the most electron-deficient 2,3-unsaturated N-acetylneuraminic acid (Neu2en) derivatives were investigated (Scheme 3). Surprisingly, when the Neu5Ac2en substrate 6a was treated under the standard conditions, the trifluoromethylated product 7a was obtained in 43% isolated yield and the starting material 6a was recovered in

surveyed, as shown in Scheme 1. To our delight, the reactions of the methylated (1b, 90%), p-methoxybenzylated (1c, 89%), Scheme 1. Scope of Trifluoromethylation of Other Protected 3,4-Dideoxy-glucals

acetylated (1d, 90%), or pivaloylated (1e, 88%) 3,4-dideoxyglycals were similar to that of 1a. The desired products (3b−e) were obtained in high yields. The structures of the trifluoromethylated-3,4-dideoxy-glycals (3b−e) were unambiguously identified by 1H, 13C, and 19F NMR analyses. Subsequently, we proceeded to study the scope of the more electron-deficient and challenging hexose-derived glycals (Scheme 2). It was found that the most satisfactory yields were obtained by increasing 2c to 3.0 equiv and the reaction time to 12 h (Table S5). Under the reoptimized conditions, the reactions of benzylated glucal/galactal/rhamnal/arabinal, and pmethoxybenzylated or methylated glucal/galactal/rhamnal/ arabinal afforded the corresponding products in 65−78%

Scheme 3. Photocatalytic C−H Trifluoromethylation of Neu2en Derivatives and Their Transformations

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DOI: 10.1021/acs.orglett.5b03016 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters 42% yield. Similarly, 2,3-unsaturated N-acetylneuraminic acid derivative 6b, which is an important precursor of antiflu drug zanamivir, was successfully trifluoromethylated to give 7b in 45% yield with 40% of 6b recovered. Deprotection of 7a and reduction of 7b produced 8a and 8b in quantitative yield and 70% yield, respectively. These results showed that the trifluoromethyl group had little influence on functional group manipulations of the Neu2en moiety. Thus, it may have promising applications in the trifluoromethylation modification of Neu2en-derived drugs. To gain insight into the reaction mechanism, a series of experiments were conducted under the standard conditions with 1a and 2c (see the Supporting Information for details). First, it was found that no reaction occurred in the absence of either light or photocatalyst, illustrating that light and the photocatalyst together triggered the trifluoromethylation reaction. Under the standard conditions, when 1a was reacted with 2c, product 3a, trifluoromethylated dibenzothiophenes (10, comprising of four isomers 10a−d), and dibenzothiophene (9a) were isolated in 91%, 11%, and 125% yield, respectively. The detection of 10a−d, which is first reported in the trifluoromethylation reaction by the use of Umemoto’s reagent as the CF3 source, accounting for the excess of 2c. The trifluoromethylation reaction of 1a with 2c was almost shut down by the addition of 2.0 equiv of TEMPO (2,2,6,6tetramethyl-1-piperidinyloxy), a well-known radical scavenger, and TEMPO−CF38n,17 was obtained in 120% yield based on 19 F NMR analysis, whereas the desired product 3a was detected only in a trace amount (see the Supporting Information). This implied that a CF3 radical intermediate was involved in the trifluoromethylation process. Moreover, the ethyl glycoside was isolated in 71% yield using ethyl alcohol as the cosolvent (Supporting Information), indicating a glycosylation process via a glycosyl oxocarbenium ion. Based on these experimental results, a possible reaction mechanism is tentatively illustrated in Scheme 4. Initially, fac-

of C or D affords the desired product E. The formation of a small amount of trifluoromethylated dibenzothiophene might result from the free-radical aromatic substitution reaction of dibenzothiophene with the CF3 radical. In conclusion, a mild, efficient, and practical reaction for the direct C−H trifluoromethylation of glycals under visible light has been reported for the first time. This photocatalytic reaction employs fac-Ir3+(ppy)3 as the photocatalyst, Umemoto’s reagent as the CF3 source, and a household blue LED or sunlight (see the Supporting Information) as the light source. Glycals bearing both electron-withdrawing and -donating protective groups were shown to be suitable substrates for the reaction. This visible light-mediated trifluoromethylation transformation was further highlighted by the trifluoromethylation of the Neu2en moiety. The possible mechanism involves a CF3 radical and a glycosyl oxocarbenium ion and was probed by a series of experiments. This novel protocol not only finds many applications in the synthesis of trifluoromethylated carbohydrates and carbohydrate-based drugs but also holds great potential in the trifluoromethylation of other electrondeficient compounds. Studies along this line are currently underway in our laboratory.

Scheme 4. Possible Reaction Mechanism

Notes

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b03016. Detailed experimental procedures and spectral data for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by grants (2012CB822100, 2013CB910700) from the Ministry of Science and Technology of China, the National Natural Science Foundation of China (Grant No. 21232002), and Beijing Higher Education Young Elite Teacher Project (YETP0063). We thank Profs. Jinbo Hu (SIOC), Ning Jiao (PKUHSC), and Suwei Dong (PKUHSC) for their helpful discussions.

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REFERENCES

(1) (a) Varki, A. Glycobiology 1993, 3, 97−130. (b) Boltje, T. J.; Buskas, T.; Boons, G.-J. Nat. Chem. 2009, 1, 611−622. (c) van Kooyk, Y.; Rabinovich, G. A. Nat. Immunol. 2008, 9, 593−601. (2) (a) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491−514. (b) Brown, J. R.; Crawford, B. E.; Esko, J. D. Crit. Rev. Biochem. Mol. Biol. 2007, 42, 481−515. (c) Stallforth, P.; Lepenies, B.; Adibekian, A.; Seeberger, P. H. J. Med. Chem. 2009, 52, 5561−5577. (3) Wong, C.-H. Carbohydrate-Based Drug Discovery; Wiley: Weinheim, 2003; Vol. 1. (4) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330. (b) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369. (c) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−1886. (d) Dax, K.; Albert, M.; Ortner, J.; Paul, B. J.

Ir3+(ppy)3 accepts a photon from the light source to form the excited state [fac-Ir3+(ppy)3]* via metal-to-ligand charge transfer (MLCT). This high-energy intermediate transfers a single electron to 2c to generate the electron-deficient facIr4+(ppy)3, CF3 radical, and dibenzothiophene (9a). Addition of the CF3 radical to the double bond of the glycal generates a glycosyl radical B, which would be oxidized by fac-Ir4+(ppy)3 to produce glycosyl oxocarbenium ion C, while returning facIr3+(ppy)3 to the catalytic cycle. The subsequent deprotonation C

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Letter

Organic Letters Carbohydr. Res. 2000, 327, 47−86. (e) Leclerc, E.; Pannecoucke, X.; Etheve-Quelquejeu, M.; Sollogoub, M. Chem. Soc. Rev. 2013, 42, 4270−4283. (f) Mun, J. Curr. Top. Med. Chem. 2013, 13, 944−950. (g) Belhomme, M.-C.; Poisson, T.; Pannecoucke, X. Org. Lett. 2013, 15, 3428−3431. (5) (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475−4521. (b) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470−477. (6) For selected recent reviews on trifluoromethylation, see: (a) Zheng, Y.; Ma, J.-A. Adv. Synth. Catal. 2010, 352, 2745−2750. (b) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950−8958. (c) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int. Ed. 2012, 51, 5048− 5050. (d) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9120−9123. (e) Landelle, G.; Panossian, A.; Pazenok, S.; Vors, J. P.; Leroux, F. R. Beilstein J. Org. Chem. 2013, 9, 2476−536. (f) Wu, X. F.; Neumann, H.; Beller, M. Chem. - Asian J. 2012, 7, 1744−1754. (g) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115, 765−825. (h) Macé, Y.; Magnier, E. Eur. J. Org. Chem. 2012, 2012, 2479−2494. (i) Nishida, T.; Ida, H.; Kuninobu, Y.; Kanai, M. Nat. Commun. 2014, 5, 3387. (j) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598−6608. (k) Egami, H.; Sodeoka, M. Angew. Chem., Int. Ed. 2014, 53, 8294− 8308. (l) Koike, T.; Akita, M. J. Fluorine Chem. 2014, 167, 30−36. (m) Barata-Vallejo, S.; Lantaño, B.; Postigo, A. Chem. - Eur. J. 2014, 20, 16806−16829. (n) Besset, T.; Poisson, T.; Pannecoucke, X. Chem. - Eur. J. 2014, 20, 16830−16845. (7) (a) Hari, D. P.; Konig, B. Angew. Chem., Int. Ed. 2013, 52, 4734− 4743. (b) Xuan, J.; Xiao, W. J. Angew. Chem., Int. Ed. 2012, 51, 6828− 6838. (c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. Chem. Rev. 2013, 113, 5322−5363. (d) Narayanam, J. M.; Stephenson, C. R. Chem. Soc. Rev. 2011, 40, 102−113. (e) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527−532. (f) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77−80. (8) For selected examples on photoredox-catalyzed trifluoromethylation, see: (a) Iqbal, N.; Jung, J.; Park, S.; Cho, E. J. Angew. Chem., Int. Ed. 2014, 53, 539−542. (b) Xu, P.; Abdukader, A.; Hu, K.; Cheng, Y.; Zhu, C. Chem. Commun. 2014, 50, 2308−10. (c) Choi, W. J.; Choi, S.; Ohkubo, K.; Fukuzumi, S.; Cho, E. J.; You, Y. Chem. Sci. 2015, 6, 1454−1464. (d) Straathof, N. J. W.; Tegelbeckers, B. J. P.; Hessel, V.; Wang, X.; Noël, T. Chem. Sci. 2014, 5, 4768−4773. (e) Wilger, D. J.; Gesmundo, N. J.; Nicewicz, D. A. Chem. Sci. 2013, 4, 3160. (f) Mizuta, S.; Verhoog, S.; Engle, K. M.; Khotavivattana, T.; O’Duill, M.; Wheelhouse, K.; Rassias, G.; Medebielle, M.; Gouverneur, V. J. Am. Chem. Soc. 2013, 135, 2505−2508. (g) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. Am. Chem. Soc. 2011, 133, 4160−4163. (h) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034−9037. (i) Lin, Q. Y.; Xu, X. H.; Qing, F. L. J. Org. Chem. 2014, 79, 10434−10446. (j) Nagib, D. A.; MacMillan, D. W. Nature 2011, 480, 224−228. (k) Carboni, A.; Dagousset, G.; Magnier, E.; Masson, G. Org. Lett. 2014, 16, 1240−1243. (l) Noto, N.; Miyazawa, K.; Koike, T.; Akita, M. Org. Lett. 2015, 17, 3710−3713. (m) Oh, S. H.; Malpani, Y. R.; Ha, N.; Jung, Y. S.; Han, S. B. Org. Lett. 2014, 16, 1310−1313. (n) Xie, J.; Yuan, X.; Abdukader, A.; Zhu, C.; Ma, J. Org. Lett. 2014, 16, 1768−1771. (o) Sahoo, B.; Li, J.-L.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 11577−11580. (9) (a) Koike, T.; Akita, M. Top. Catal. 2014, 57, 967−974. (b) Cantillo, D.; de Frutos, O.r; Rincon, J. A.; Mateos, C.; Kappe, C. O. Org. Lett. 2014, 16, 896−899. (10) (a) Wegert, A.; Reinke, H.; Miethchen, R. Carbohydr. Res. 2004, 339, 1833−1837. (b) Hiraoka, S.; Yamazaki, T.; Kitazume, T. Chem. Commun. 1997, 1497−1498. (c) Eilitz, U.; Böttcher, C.; Hennig, L.; Burger, K.; Haas, A.; Gockel, S.; Sieler, J. J. Heterocycl. Chem. 2003, 40, 329−335. (d) Foulard, G.; Brigaud, T.; Portella, C. J. Org. Chem. 1997, 62, 9107−9113. (e) Hiraoka, S.; Yamazaki, T.; Kitazume, T. Synlett 1997, 1997, 669−670. (11) (a) Huang, X.; Huang, L.; Wang, H.; Ye, X.-S. Angew. Chem., Int. Ed. 2004, 43, 5221−5224. (b) Yan, R.-B.; Wu, Y.-F.; Liu, J.; Zhang, X.L.; Ye, X.-S. Chin. Chem. Lett. 2013, 24, 273−278. (c) Wang, G.-N.; Reinkensmeier, G.; Zhang, S.-W.; Zhou, J.; Zhang, L.-R.; Zhang, L.-H.; Butters, T. D.; Ye, X.-S. J. Med. Chem. 2009, 52, 3146−3149. (d) Ye,

X.-S.; Sun, F.; Liu, M.; Li, Q.; Wang, Y.; Zhang, G.; Zhang, L.-H.; Zhang, X.-L. J. Med. Chem. 2005, 48, 3688−3691. (e) Xiong, D.-C.; Zhang, L.-H.; Ye, X.-S. Org. Lett. 2009, 11, 1709−1712. (12) (a) Seeberger, P. H.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685−695. (b) Danishefsky, S. J.; Allen, J. R. Angew. Chem., Int. Ed. 2000, 39, 836−863. (c) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576−1624. (d) Xiang, S.; Hoang, K. L. M.; He, J.; Tan, Y. J.; Liu, X.-W. Angew. Chem., Int. Ed. 2015, 54, 604−607. (e) Cheshev, P.; Marra, A.; Dondoni, A. Carbohydr. Res. 2006, 341, 2714−2716. (f) Flasz, J. T.; Hale, K. J. Org. Lett. 2012, 14, 3024−3027. (13) (a) Chenault, H. K.; Mandes, R. F. Bioorg. Med. Chem. 1994, 2, 627−629. (b) Lai, E. C. K.; Morris, S. A.; Street, I. P.; Withers, S. G. Bioorg. Med. Chem. 1996, 4, 1929−1937. (c) Stolz, F.; Reiner, M.; Blume, A.; Reutter, W.; Schmidt, R. R. J. Org. Chem. 2004, 69, 665− 679. (14) (a) Woods, J. M.; Bethell, R. C.; Coates, J. A.; Healy, N.; Hiscox, S. A.; Pearson, B. A.; Ryan, D. M.; Ticehurst, J.; Tilling, J.; Walcott, S. M. Antimicrob. Agents Chemother. 1993, 37, 1473−1479. (b) El-Deeb, I. M.; Guillon, P.; Winger, M.; Eveno, T.; Haselhorst, T.; Dyason, J. C.; von Itzstein, M. J. Med. Chem. 2014, 57, 7613−7623. (c) Guillon, P.; Dirr, L.; El-Deeb, I. M.; Winger, M.; Bailly, B.; Haselhorst, T.; Dyason, J. C.; von Itzstein, M. Nat. Commun. 2014, 5, 5268. (15) Honda, T.; Masuda, T.; Yoshida, S.; Arai, M.; Kaneko, S.; Yamashita, M. Bioorg. Med. Chem. Lett. 2002, 12, 1925−1928. (16) Mendel, D. B.; Tai, C. Y.; Escarpe, P. A.; Li, W.; Sidwell, R. W.; Huffman, J. H.; Sweet, C.; Jakeman, K. J.; Merson, J.; Lacy, S. A.; Lew, W.; Williams, M. A.; Zhang, L.; Chen, M. S.; Bischofberger, N.; Kim, C. U. Antimicrob. Agents Chemother. 1998, 42, 640−646. (17) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410−16413.

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